In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat

Li, Chunze; Grillo, Mark P.; Benet, Leslie Z.

doi:10.1124/jpet.102.043174

Cited by 30 publications

(28 citation statements)

References 26 publications

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“…Two hours after administration of Tol, the rats were sacrificed by cervical dislocation, and the livers were removed and snap-frozen in liquid nitrogen. The livers were processed essentially as described by Li et al (2003). In brief, 1.0 g of liver was homogenized in 3.0 ml of 0.05 M KH 2 PO 4 (pH 4.5, 0°C) to which 200 l of 20% phosphoric acid was added.…”

Section: Methodsmentioning

confidence: 99%

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Olsen

Li²,

Skonberg³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Carboxylic acids may be metabolized to acyl glucuronides and acyl-coenzyme A thioesters (acyl-CoAs), which are reactive metabolites capable of reacting with proteins in vivo. In this study, the metabolic activation of tolmetin (Tol) to reactive metabolites and the subsequent formation of Tol-protein adducts in the liver were studied in rats. Two hours after dose administration (100 mg/kg i.p.), tolmetin acyl-CoA (Tol-CoA) was identified by liquid chromatography-tandem mass spectrometry in liver homogenates. Similarly, the acyl-CoA-dependent metabolites tolmetin-taurine conjugate (Tol-Tau) and tolmetin-acyl carnitine ester (Tol-Car) were identified in rat livers. In a rat bile study (100 mg/kg i.p.), the S-acyl glutathione thioester conjugate was identified, providing further evidence of the formation of reactive metabolites such as Tol-CoA or Tol-acyl glucuronide (Tol-O-G), capable of acylating nucleophilic functional groups. Three rats were treated with clofibric acid (150 mg/kg/day i.p. for 7 days) before dose administration of Tol. This resulted in an increase in covalent binding to liver proteins from 0.9 nmol/g liver in control rats to 4.2 nmol/g liver in clofibric acidtreated rats. Similarly, levels of Tol-CoA increased from 0.6 nmol/g to 4.4 nmol/g liver after pretreatment with clofibric acid, whereas the formation of Tol-O-G and Tol-Tau was unaffected by clofibric acid treatment. However, Tol-Car levels increased from 0.08 to 0.64 nmol/g after clofibric acid treatment. Collectively, these results confirm that Tol-CoA is formed in vivo in the rat and that this metabolite can have important consequences in terms of covalent binding to liver proteins.Drugs with a carboxylate functional group can be metabolized to chemically reactive metabolites that react with nucleophilic amino acids of proteins to form drug-protein adducts (Boelsterli, 2002;Bailey and Dickinson, 2003). Tolmetin (Tol; 5-[4Ј-methylbenzoyl]-1-methylpyrrole-2-acetic acid) is an example of a carboxylic acidcontaining drug which, in humans, is partly metabolized to the acyl glucuronide (Hyneck et al., 1987). In vitro studies have shown that the tolmetin-acyl glucuronide (Tol-O-G) is a reactive metabolite that reacts with the amino acid side chains of lysine, arginine, and serine present in human serum albumin (Ding et al., 1993(Ding et al., , 1995.Covalent binding of Tol has also been studied in humans, where Tol-protein adducts have been detected in plasma (Hyneck et al., 1988;Zia-Amirhosseini et al., 1994). Tol-protein adducts in plasma were believed to result from reaction of the acyl glucuronide with plasma proteins, since a good correlation between covalent plasmaprotein adducts and exposure to Tol-O-G was observed (Hyneck et al., 1988). In the liver, other metabolic pathways may contribute to Tol-protein adduct formation. In a recent study, it has been shown that the pyrrole moiety of Tol may undergo bioactivation to a reactive arene oxide (Chen et al., 2006). Other reports have shown that acyl-coenzyme A thioesters (acyl-CoAs) a...

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Section: Methodsmentioning

confidence: 99%

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Olsen

Li²,

Skonberg³

et al. 2007

Drug Metab Dispos

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“…Covalent binding of 2-PPA to tissue proteins was measured by scintillation counting of exhaustively washed protein precipitates as described previously (Li et al, 2003b). 2-PPA-CoA and acyl glucuronide formation in rat livers was determined by the previously described method (Li et al, 2003b).…”

Section: Effects Of Fibrates On Metabolic Activation Of 2-ppamentioning

confidence: 99%

“…2-PPA-CoA and acyl glucuronide formation in rat livers was determined by the previously described method (Li et al, 2003b).…”

Section: Effects Of Fibrates On Metabolic Activation Of 2-ppamentioning

confidence: 99%

“…Our previous studies showed that the extent of covalent binding of 2-PPA to hepatic protein was markedly decreased when the corresponding acyl-CoA formation was inhibited by trimethylacetic acid (Li et al, 2003b). It is unknown, however, whether the agents that potentially up-regulate acyl-CoA pathways could enhance the extent of covalent binding.…”

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confidence: 99%

“…Comparative in vitro studies with several carboxylic acids, including clofibric acid (Shore et al, 1995;Grillo and Benet, 2001), 2-PPA (Li et al, 2002b), and naproxen (Olsen et al, 2002), showed that acyl-CoA thioesters are 40-to 70-fold more reactive toward glutathione, forming acyl glutathione conjugates, than the respective acyl glucuronides in vitro in buffer. In the case of 2-PPA, metabolic activation by acyl-CoA formation has been shown to contribute more to covalent binding than the corresponding acyl glucuronidation in vitro in hepatocytes (Li et al, 2002a) and in vivo in rats (Li et al, 2003b).…”

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Differential Effects of Fibrates on the Metabolic Activation of 2-Phenylpropionic Acid in Rats

Grillo²,

Badagnani³

et al. 2008

Drug Metab Dispos

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ABSTRACT:A series of studies were conducted to explore the inductive potential of different fibric acid derivatives on the two alternative metabolic activation pathways of 2-phenylpropionic acid (2-PPA) (a model substrate for profen drugs), namely acyl-CoA formation and acyl glucuronidation, in vivo in rats, and to evaluate whether such treatment could potentially modulate the covalent binding of pro-

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Bioactivation by Phase‐II‐Enzyme‐Catalyzed Conjugation of Xenobiotics

Grillo

2012

Encyclopedia of Drug Metabolism and Interactions

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Phase‐II‐enzyme‐catalyzed conjugation of xenobiotics with endogenous cofactors leads to hydrophilic derivatives that, in most cases, functions in the elimination and detoxification of xenobiotics from the body. However, this process can also mediate their bioactivation to chemically‐reactive and hence potentially toxic metabolites. The major conjugation reactions known to be involved in xenobiotic bioactivation are glucuronidation, sulfonation, acetylation, GSH conjugation, and acyl‐S‐CoA formation. Chemically‐reactive metabolites of xenobiotics can lead to covalent binding to protein and/or nucleic acids which some cases leads to intrinsic and/or idiosyncratic toxicity and carcinogenicity. This chapter will cover the known mechanisms of xenobiotic bioactivation by phase‐II‐drug‐conjugating enzymes.

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In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat

Cited by 30 publications

References 26 publications

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Differential Effects of Fibrates on the Metabolic Activation of 2-Phenylpropionic Acid in Rats

Bioactivation by Phase‐II‐Enzyme‐Catalyzed Conjugation of Xenobiotics

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